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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Adverse effects of benzodiazepines are largely mediated by GABAA receptors containing \u03b11-subunits. Recent efforts to replace benzodiazepines with neurosteroids are promising, but it is unclear to what extent \u03b11-GABAA receptors are also upregulated by neurosteroids. Here, we investigate how a prototypical benzodiazepine and neurosteroids modify a form of neuronal activity that is controlled by \u03b11-GABAA receptors. We compared the actions of the benzodiazepine midazolam, the naturally occurring neurosteroid allopregnanolone, and XBD173, a drug that enhances neurosteroidogenesis, on high- (HFA, &gt;50 Hz) and low- (LFA, &lt;50 Hz) frequency action potential activity in cultured neocortical tissue slices derived from wild-type mice via extracellular multi-unit recordings. The effects of midazolam were also quantified in slices from \u03b12\/3\/5-knock-in-mice, in which the drug acts almost exclusively via \u03b11-GABAA receptors. In slices derived from \u03b12\/3\/5-knock-in mice, low nanomolar concentrations of midazolam suppressed HFA in a selective manner. In slices derived from wild-type animals, HFA was also attenuated by midazolam. In contrast, allopregnanolone and XBD173 did not affect HFA but strongly suppressed LFA. Our findings suggest that, in contrast to benzodiazepines, neurosteroids do not dampen HFA, a type of cortical network activity tightly controlled by \u03b11-GABAA receptors.<\/jats:p>","DOI":"10.3390\/ijms27156941","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Modulation of High- and Low-Frequency Activity by Midazolam and Neurosteroids in Neocortical Slices"],"prefix":"10.3390","volume":"27","author":[{"given":"Stefan","family":"Bieletzki","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology Section, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Gotthard","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology Section, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X\u00e8nia","family":"Puig-Bosch","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Medical School, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany"},{"name":"Artificial Intelligence in Medicine Lab (BCN-AIM), Departament de Matem\u00e0tiques i Inform\u00e0tica, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6954-4629","authenticated-orcid":false,"given":"Hanns Ulrich","family":"Zeilhofer","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland"},{"name":"Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Z\u00fcrich, 8092 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9396-4746","authenticated-orcid":false,"given":"Uwe","family":"Rudolph","sequence":"additional","affiliation":[{"name":"Department of Comparative Biosciences, College of Veterinary Medicine, and Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1698-4257","authenticated-orcid":false,"given":"Gerhard","family":"Rammes","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Medical School, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Antkowiak","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology Section, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-1511","authenticated-orcid":false,"given":"Berthold","family":"Drexler","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care Medicine, Experimental Anesthesiology Section, Eberhard Karls University, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1038\/nrd3502","article-title":"Beyond classical benzodiazepines: Novel therapeutic potential of GABAA receptor subtypes","volume":"10","author":"Rudolph","year":"2011","journal-title":"Nat. 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